Occult lymph node metastases and racial disparities in colon cancer outcomes

描述（由申请人提供）：本申请涉及广泛的挑战领域（09）：健康差异和预防以及具体的挑战主题，09-CA-101：癌症发病率差异的基础。与高加索人相比，非裔美国人的特定阶段结局存在明显差异，结直肠癌是美国第三大最常见的癌症事件和第三大癌症死亡原因。事实上，无转移的非裔美国人因种族原因死亡率高出40%。导致这些结果种族差异的因素以及量化过度风险的方法仍然不明确。虽然结直肠癌中最重要的生存预后标志物和对治疗反应的预测标志物是组织学检测到的局部淋巴结中的肿瘤细胞，但约30%的组织学阴性淋巴结（I、II期; pN 0）患者死于复发性疾病，反映了未被检测到的分期不足和隐匿性淋巴结转移。最近，在一项前瞻性、多中心、盲法临床试验中，通过定量RT-PCR（qRT-PCR），临床验证了GUCY 2C（一种表达通常仅限于肠细胞，但在结直肠癌细胞中普遍表达的蛋白质）可用于检测具有重要临床意义的隐匿性转移。此外，除了将隐匿性转移作为分类变量（是/否）的效用之外，通过GUCY 2C qRT-PCR分层风险估计隐匿性肿瘤负荷（多少），识别具有接近零风险的pN 0患者和具有>80%风险的患者，具有不利结局。重要的是，亚组分析表明，非裔美国人在淋巴结中表现出不成比例的隐匿性肿瘤负荷，与不利的临床结局相关。这里的工作假设表明，pN 0结直肠癌分期特异性结局的种族差异部分反映了不成比例的分期不足和淋巴结中的隐匿性转移，这可以通过GUCY 2C qRT-PCR检测到。在这里，我们提出了一个回顾性分析pN 0的非裔美国人和高加索人结肠癌患者>5年的分期，与确定的临床结果，以量化的结果种族差异的隐匿性转移的贡献。该提案将检查GUCY 2C qRT-PCR作为分类变量（是/否）的效用，该分类变量可识别淋巴结中的隐匿性转移，该转移可归因于pN 0结肠癌患者的种族过度风险。此外，我们将量化隐匿性肿瘤负荷（多少）对pN 0患者结局种族差异的贡献。最后，将确定淋巴结中隐匿性转移性肿瘤细胞对结肠癌分期特异性结局种族差异的贡献，并将对包括GUCY 2C qRT-PCR在内的用于量化非裔美国人中隐匿性肿瘤负荷和过度风险的预后范例进行临床验证和定位。项目叙述：与白人相比，患有结肠癌的非洲裔美国人的死亡率增加，尽管原因尚不清楚。在这种情况下，最近的工作揭示了淋巴结中的隐匿性转移的重要性，这些转移在确定结肠癌患者的疾病复发风险时无法被常规技术检测到。目前的研究探讨了通过新的分子技术检测到的隐匿性转移对非裔美国人和白人结肠癌患者结局的种族差异的贡献。

DESCRIPTION (provided by applicant): This application addresses Broad Challenge Area (09): Health Disparities and Prevention and Specific Challenge Topic, 09-CA-101: The Basis for Differences in Cancer Incidence. There is an established disparity in stage-specific outcomes in African Americans, compared to Caucasians, with colorectal cancer, the 3rd most common incident cancer and the 3rd leading cause of cancer death in the U.S. Indeed, African Americans who are free of metastases exhibit a 40% excess mortality attributable to race. Factors contributing to these racial disparities in outcomes, and methods that quantify excess risk, remain undefined. While the most important prognostic marker of survival and predictive marker of response to therapy in colorectal cancer are tumor cells in regional lymph nodes detected histologically, ~30% of patients with histology-negative nodes (stage I, II; pN0) die of recurrent disease, reflecting under-staging and occult nodal metastases that escape detection. Recently, GUCY2C, a protein whose expression is restricted to intestinal cells normally, but is universally expressed by colorectal cancer cells, was clinically validated for detection of prognostically important occult metastases, by quantitative RT-PCR (qRT-PCR), in a prospective, multicenter, blinded clinical trial. Further, beyond the utility of occult metastases as a categorical variable (yes/no), occult tumor burden (how much) estimated by GUCY2C qRT-PCR stratified risk, identifying pN0 patients with near-zero risk, and those with >80% risk, of unfavorable outcomes. Importantly, subgroup analysis suggests that African Americans exhibit disproportionate occult tumor burden in lymph nodes associated with unfavorable clinical outcomes. The working hypothesis here suggests that racial disparities in stage-specific outcomes in pN0 colorectal cancer, in part, reflect disproportionate under-staging and occult metastases in lymph nodes which can be detected by GUCY2C qRT-PCR. Here, we propose a retrospective analysis of pN0 African American and Caucasian colon cancer patients >5 y beyond staging, with established clinical outcomes, to quantify the contribution of occult metastases to racial disparities in outcomes. This proposal will examine the utility of GUCY2C qRT-PCR as a categorical variable (yes/no) that identifies occult metastases in lymph nodes contributing to excess risk attributable to race in patients with pN0 colon cancer. Moreover, we will quantify the contribution of occult tumor burden (how much) to racial differences in outcomes in pN0 patients. At the conclusion, the contribution of occult metastatic tumor cells in lymph nodes to racial disparities in stage-specific outcomes in colon cancer will be defined, and a prognostic paradigm comprising GUCY2C qRT-PCR to quantify occult tumor burden and excess risk in African Americans will be clinically validated and positioned for translation. PROJECT NARRATIVE: African Americans with colon cancer exhibit increased mortality compared to Caucasians, although the reasons are unknown. In that context, recent work revealed the importance of occult metastases in lymph nodes that are undetected by routine techniques in defining the risk of disease recurrence in patients with colon cancer. The present studies examine the contribution of occult metastases, detected by new molecular techniques, to racial disparities in outcomes in African Americans and Caucasians with colon cancer.